ABSTRACT
Mitochondria provide energy for all cellular processes, including reactions associated with cell cycle progression, DNA damage repair, and cilia formation. Moreover, mitochondria participate in cell fate decisions between death and survival. Nek family members have already been implicated in DNA damage response, cilia formation, cell death, and cell cycle control. Here, we discuss the role of several Nek family members, namely Nek1, Nek4, Nek5, Nek6, and Nek10, which are not exclusively dedicated to cell cycle-related functions, in controlling mitochondrial functions. Specifically, we review the function of these Neks in mitochondrial respiration and dynamics, mtDNA maintenance, stress response, and cell death. Finally, we discuss the interplay of other cell cycle kinases in mitochondrial function and vice versa. Nek1, Nek5, and Nek6 are connected to the stress response, including ROS control, mtDNA repair, autophagy, and apoptosis. Nek4, in turn, seems to be related to mitochondrial dynamics, while Nek10 is involved with mitochondrial metabolism. Here, we propose that the participation of Neks in mitochondrial roles is a new functional axis for the Nek family.
Subject(s)
Mitochondria , Protein Serine-Threonine Kinases , NIMA-Related Kinases/metabolism , Protein Serine-Threonine Kinases/metabolism , Mitochondria/metabolism , Homeostasis , DNA, MitochondrialSubject(s)
Anti-Inflammatory Agents/therapeutic use , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Primaquine/therapeutic use , Analysis of Variance , Animals , Calcium-Binding Proteins/metabolism , Central Nervous System/drug effects , Central Nervous System/metabolism , Central Nervous System/pathology , Cytokines/metabolism , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/chemically induced , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/pathology , Forkhead Transcription Factors/metabolism , Freund's Adjuvant/toxicity , Glial Fibrillary Acidic Protein/metabolism , Mice , Mice, Inbred C57BL , Microfilament Proteins/metabolism , Myelin-Oligodendrocyte Glycoprotein/toxicity , Nerve Tissue Proteins/metabolism , Peptide Fragments/toxicity , Severity of Illness Index , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/metabolismABSTRACT
Dendritic cells (DCs) are professional antigen-presenting cells specifically targeted during Plasmodium infection. Upon infection, DCs show impaired antigen presentation and T-cell activation abilities. In this study, we aimed to evaluate whether cellular extracts obtained from Plasmodium berghei-infected erythrocytes (PbX) modulate DCs phenotypically and functionally and the potential therapeutic usage of PbX-modulated DCs in the control of experimental autoimmune encephalomyelitis (EAE, the mouse model for human multiple sclerosis). We found that PbX-treated DCs have impaired maturation and stimulated the generation of regulatory T cells when cultured with naive T lymphocytes in vitro. When adoptively transferred to C57BL/6 mice the EAE severity was reduced. Disease amelioration correlated with a diminished infiltration of cytokine-producing T cells in the central nervous system as well as the suppression of encephalitogenic T cells. Our study shows that extracts obtained from P. berghei-infected erythrocytes modulate DCs towards an immunosuppressive phenotype. In addition, the adoptive transfer of PbX-modulated DCs was able to ameliorate EAE development through the suppression of specific cellular immune responses towards neuro-antigens. To our knowledge, this is the first study to present evidence that DCs treated with P. berghei extracts are able to control autoimmune neuroinflammation.
